Loss of the DNA-binding function of estrogen receptor (ER) has been observed in 40% of ER-positive breast tumors and is postulated to be a major reason why many ER-positive breast cancer patients fail to respond when the antiestrogen tamoxifen is given as first-line therapy for recurrent disease. The objective of our project is to identify and characterize the post-translational molecular mechanism(s) accounting for the observed defect in ER-DNA binding function, enabling the design of future therapeutic modalities to reverse or prevent this ER defect and thereby restore endocrine sensitivity.